Asymmetric synthesis has become increasingly important in the pharmaceutical industry. There is growing regulatory pressure to approve only those enantiomers of drugs that have the desired biological activity. For safety reasons and to demonstrate efficacy, regulatory agencies are taking the position that only those enantiomers with pharmaceutical action should be administered, apart from the enantiomers with little or no action or even adverse or toxic effect. The total market for enantiomerically pure pharmaceuticals is close to ninety billion U.S. dollars. To prepare large quantities of drugs via classical resolution is often cost prohibitive, and such drugs will commonly be prepared via asymmetric synthesis.
Many asymmetric syntheses involve the use of catalysts, and typically employ chiral ligands and late transition metals. Asymmetric hydrogenation is a synthetic transformation that has been used industrially on large scale (see Asymmetric Catalysis on Industrial Scale, H. U. Blaser and E. Schmidt, Eds., Wiley-VCH, 2004), usually utilizing so-called “functionalized olefins”, that is, olefins that contain some additional close functionality, such as unsaturated esters, enamides, enecarbamates, and dehydroaminoester and dehydroaminoacid derivatives. These are discussed in a good recent review on the topic (Comprehensive Asymmetric Catalysis, Vol. 1, pp. 121-182, E. N. Jacobsen, A. Pfaltz, H. Yamamaoto, Eds., Springer-Verlag, 1999).
Some of the most successful commercial ligands for this type of asymmetric hydrogenation are 1) The DuPhos family of ligands (for a review, see: Burk, M. J. Chemtracts 1998, 11(11), 787.) 2) The Zhang ligands such as TangPhos and DuanPhos (Zhang, X.; Tang, W. Chemical Reviews 2003, 103(8), 3029. 3) The Josiphos family of ligands from Solvias (for a review, see: Blaser, H.-U. et al Topics in Catalysis 2002, 19(1), 3.) 4) BINAP and it's derivatives (for reviews, see: a) Noyori, R.; Adv. Syn. Catalysis 2003, 345 (1+2), 15. b) Saito, T. et al, Synlett 2001, 1055) and 5) Dipamp (for a review, see: Knowles, W. S., Angew. Chem. Int. Ed. 2002, 41(12), 1998.).

Bidentate ligands play a central role in catalyst design for asymmetric synthesis, because they can hold the metal in a relatively rigid and defined spatial environment. Almost all successful ligands for asymmetric hydrogenation are of the “P-P” type, that is, the metal atom binds to two phosphorus atoms. For the P-P ligands in the literature, the most common metals used are rhodium, iridium, and ruthenium, with rhodium being most commonly employed and often preferred.
U.S. Pat. No. 6,316,620 discloses a class of electronically-tunable chiral ligands (BIPI Ligands) of the “P-N” type (1). A typical example is shown below. This ligand platform has an advantage over the systems just named: it's electronic properties can be
dramatically altered just by changing the substituent on the imidazoline nitrogen atom. If this N-substituent is an alkyl group, for example, the ligand will be basic and a “strong” donor, while an acyl N-substituent, for example, will lead to a neutral ligand that is a weaker donor. These electronic properties can therefore be “tuned” for different types of asymmetric transformations as needed. We have demonstrated the successful use of this electronic tuning concept in the asymmetric Heck Reaction ((a) C. Busacca et al, Org. Lett. 2003, 5(4), 595. b) C. Busacca, et al J. Org. Chem. 2004, 69(16), 5187.)), and Pfaltz has shown the use of the BIPI Ligands (Org. Lett. 2002, 4(26), 4713) for asymmetric hydrogenation of unfunctionalized olefins.
There is interest in the use of electronically tunable chiral ligands for the asymmetric hydrogenation of dehydrourea esters, such as 1 below. Asymmetric hydrogenation of this class of olefins does not appear to have been studied previously. As shown in Scheme 1a, the product 3 is formed after the initial adduct 2, is further hydrogenated to reduce the terminal olefin. The chirality-inducing event is the first step.
